Blast related traumatic brain injury (TBI) has been a major cause of injury in the wars in Iraq and Afghanistan. A striking feature of the mild TBI cases has been the prominent association with post- traumatic stress disorder (PTSD). However, due to the overlapping symptoms distinction between the two disorders has been difficult. Collaborators at our center have characterized a rat model of mTBI in which adult male rats were exposed to repetitive blast injury while under general anesthesia. Blast exposure induced a variety of PTSD-related behavioral traits. In preliminary studies, we have demonstrated that BCI-632/MGS0039 has A42-lowering effects in vitro and in vivo as well as pro-cognitive effects in vivo. Based on these results, we predicted that the group II mGluR inhibitor BCI-632/MGS0039 (or the optimized pro-drug, BCI-838/MGS0210) would attenuate accumulation. In preparation for moving to the rat model, we studied a transgenic mouse model in which we demonstrated not only robust brain A-reduction activity, but surprisingly robust anxiolytic activity (as measured by Time in Open Arm, left panel below), pro-cognitive activity (Time Exploring Novel Object, center panel below), and pro-neurogenesis activity (Ki67-positive cells, right panel below). We now propose to move into the blast exposed rat model where we will test the ability of the drug to mitigate the anxiety phenotype in our blast exposed rats through its pro-cognitive, anxiolytic, and hippocampal pro-neurogenic activities. We propose the following specific aims: Specific Aim 1. To evaluate effects of a clinically promising group II mGluR inhibitor (BCI-632/MGS0039) on APP/ metabolism in vitro using primary neuronal culture in order to establish the mechanism of action of the drug in intact neurons; Specific Aim 2a. To evaluate the in vivo effects in a rodent model of blast-related mTBI/PTSD of the optimized BCI- 838/MGS0210 pro-drug that is metabolized to the active drug BCI-632/MGS0039, a group II mGluR inhibitor. The behavioral profile will include standard Kawarabayashi et al A protocol, including A oligomers and immunoprecipitation-mass spectrometry, following chronic treatment, morphometry of structural pathology, and BrdU and anti-doublecortin analysis for hippocampal neurogenesis. Nontransgenic Long-Evans rats will be studied employing prophylactic and treatment drug protocols before or after exposure of rats to blast TBI. Specific Aim 2b. Pilot experiments will be performed to evaluate the feasibility of mice as test animals in this model of blast-related mTBI/PTSD. Wildtype and 3xTg mice will be used, in preparation for future projects in which genetically manipulated mice will be exposed to TBI.